Ultrasound is a valuable diagnostic imaging technique for studying various areas of the body including, for example, the vasculature, such as tissue microvasculature. Ultrasound provides certain advantages over other diagnostic techniques. For example, diagnostic techniques involving nuclear medicine and X-rays generally results in exposure of the patient to ionizing electron radiation. Such radiation can cause damage to subcellular material, including deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins. Ultrasound does not involve such potentially damaging radiation. In addition, ultrasound is relatively inexpensive as compared to other diagnostic techniques, such as magnetic resonance imaging (MRI), which can require elaborate and expensive equipment.
Ultrasound involves the exposure of a patient to sound waves. Generally, the sound waves dissipate due to absorption by body tissue, penetrate through the tissue, or reflect off of the tissue. The reflection of sound waves off of tissue, generally referred to as backscatter or reflectivity, forms the basis for developing an ultrasound image. This is because sound waves reflect differentially from different body tissues. This differential reflection is due to various factors, including the constituents and the density of the particular tissue being observed. The differentially reflected waves are then detected, usually with a transducer which can detect sound waves having a frequency of from 1 megahertz (MHz) to ten MHz. The detected waves are integrated, quantitated and converted into an image of the tissue being studied.
Ultrasound imaging techniques often involve the use of contrast agents. Contrast agents can serve to improve the quality and usefulness of images which are obtained with ultrasound. Certain exemplary contrast agents include, for example, suspensions of solid particles and emulsified liquid droplets.
The reflection of sound from a liquid-gas interface is extremely efficient.
Accordingly, certain bubbles, including certain gas-filled bubbles, can be highly useful as contrast agents. The term "bubbles", as used herein, refers to vesicles which are generally characterized by the presence of one or more membranes or walls surrounding an internal void that is filled with a gas or precursor thereto. Exemplary bubbles include, for example, liposomes, micelles and the like.
The effectiveness of bubbles as contrast agents depends upon various factors, including, for example, the size of the bubble. As known to the skilled artisan, the signal which is in the range of diagnostic ultrasound frequencies and which can be reflected off of a bubble is a function of the radius (r.sup.6) of the bubble (Rayleigh Scatterer).
Thus, a bubble having a diameter of about 4 micrometer (.mu.m) possesses about 64 times the scattering ability of a bubble having a diameter of about 2 .mu.m. Thus, generally speaking, the larger the bubble, the greater the reflected signal.
However, bubble size is limited by the diameter of capillaries through which the bubbles must pass. Generally, contrast agents which comprise bubbles having a diameter of greater than about 10 .mu.m can be dangerous since microvessels may be occluded. Accordingly, it is desired that greater than about 98% of the bubbles in a contrast agent have a diameter of less than about 10 .mu.m. Mean bubble diameter is important also, and should be greater than about 1 .mu.m, with greater than about 2 .mu.m being preferred. The volume weighted mean diameter of the bubbles should be about 7 to about 20 .mu.m.
The viability of currently available ultrasound contrast agents and methods involving their use is highly dependent on the concentration of contrast agent which is present at the region being imaged. For example, ultrasound imaging involving excess concentrations of contrast agent or insufficient concentrations of contrast agent can result in the generation of ultrasound images which are unacceptable for diagnostic use. In this connection, an excess concentration of contrast agent generally results in the reflection of an overabundance of sound waves. This overabundance of reflected sound waves can cause diagnostic artifacts including, for example, shadowing or darkening, in the resulting ultrasound image. An insufficient concentration of contrast agent generally results in the reflection of an insufficient amount of sound waves. This insufficient amount of reflected sound waves can also produce diagnostic artifacts, such as excessive lightening or brightening, in the resulting ultrasound image. Methods for regulating the concentration of contrast agent in vivo in connection with diagnostic imaging methods have been unreported heretofore.
In addition to ultrasound, computed tomography (CT) is a valuable diagnostic imaging technique for studying various areas of the body. In CT, the radiodensity (electron density) of matter is measured and is expressed in terms of Hounsefield Units (HU). Hounsefield Units, named after the inventor of the first CT scanner, are an indication of the relative absorption of CT X-rays by matter, the absorption being directly proportional to the electron density of that matter. Water, for example, has a value of 0 HU, air a value of -1000 HU, and dense cortical bone a value of 1000 HU. Because of the similarity in the densities of various tissues in the body, however, it has been necessary to develop contrast agents which can be used to change the relative densities of different tissues. This has resulted in an overall improvement in the diagnostic efficacy of CT.
In the search for contrast agents for CT, researchers have generally sought to develop agents that will increase electron density in certain areas of a region of the body (positive contrast agents). Barium and iodine compounds, for example, have been developed for this purpose. For the gastrointestinal tract, barium sulfate is used extensively to increase the radiodensity of the bowel lumen on CT scans. Iodinated water-soluble contrast media are also used to increase density within the gastrointestinal tract, but are not used as commonly as the barium compounds, primarily because the iodine preparations are more expensive than barium and are generally less effective in increasing radiodensity within this region of the body. The use of low density microspheres as CT contrast agents has also been reported. See, e.g., Unger, U.S. Pat. No. 5,205,290.
As discussed above in connection with ultrasound diagnostic methods, the viability of currently available CT contrast agents and methods involving their use is extremely dependent on concentration. For example, too little contrast is observed if the concentration of contrast agent at the region of interest is too low. Conversely, too much contrast is observed if the concentration of contrast agent at the region of interest is too high. In the case of barium and iodine compounds, for example, too high a concentration can cause beam hardening diagnostic artifacts which appear as streaks in the CT images.
Accordingly, new and/or better diagnostic imaging methods which permit the regulation of the concentration of contrast agents are needed. The present invention is directed to this, as well as other, important ends.